The goals of this project are to discover the molecular mechanisms of the inherited behavioral differences to administered ethanol in both man and animals. In this process much is learned about the mechanisms of ethanol's action on the central nervous system as well. The long-term objective is to provide a rational basis for the identification of those individuals at risk of developing alcoholism as well as to provide for the prevention and treatment of ethanol's acute and chronic effects. The techniques rely heavily upon the use of animal as human genetics. Inbred strains heterogenous stocks, selected lines, recombinant inbred strain-of mice and rats are used. By the use of the technique of selective breeding in animals it has been possible to develop lines of both mice and rats that differ widely in the sensitivity of the central nervous system to an initial dose of ethanol. Recombinant inbred animals from the mouse lines bred for differences in initial sensitivity (short sleep SS and long sleep LS) will be available for detailed genetic analysis. Selective breeding of rats for the same purpose is proceeding in an independent project. Selective breeding for withdrawal sensitivity has produced mice that will allow us to carry out the same type of detailed genetic and molecular analysis of withdrawal that we have accomplished with problems of initial sensitivity. Analysis of the brains of the SS and LS mice by the techniques of neuropharmacology, neurophysiology, neurochemistry, enzymology and protein chemistry has let us to the decision to concentrate in the upcoming period on the molecular actions of ethanol with relationship to the GABA- chloride channel mechanisms and the role of intracellular calcium in the acute actions of ethanol. Initial studies on the extrapolation to humans of the findings with animals on acute sensitivity and development of acute tolerance to humans has nearly been completed. In the upcoming period we will start a new project in study of withdrawal in humans to compliment our studies of withdrawal mechanism in selected lines of mice.